Methylmercury cytotoxicity in PC12 cells is mediated by primary glutathione depletion independent of excess reactive oxygen species generation

Toxicology
Rita GattiGuido Orlandini

Abstract

Low doses, chronic exposure to mercurial organic compounds is a worldwide health concern and could be pathogenetically relevant as co-factor in several neurodegenerative diseases. In this in vitro study we wanted to further improve our knowledge on the mechanisms of toxicity of methylmercury hydroxide (MeHgOH) in the unprimed PC12 cell line. Cell viability, mitochondrial function, redox state, and cell morphology were recorded at different time points to sequence the events leading to cell death. The lowest cytotoxic concentration and EC50 were 0.3 and 1.3 microM, respectively. 5 microM MeHgOH was fatal for 80% of the cell population after 24 h; within 1 h it caused glutathione (GSH) depletion and a partial dissipation of Deltapsim. At this concentration, reactive oxygen species (ROS) generation was only slight and delayed. After 6h more than 50% of ATP was available and caspase 3 was active. Time-lapse confocal microscopy showed that only a fraction of the cells completed apoptosis while others turned toward necrosis (necrapoptosis). Pre-incubation with N-acetylcysteine (NAC) and GSH but not Cyclosporin A rescued over 80% of the cells. These results provide experimental evidence that, in this cell model, MeHgOH triggers cell d...Continue Reading

References

Oct 14, 1994·Biochemical and Biophysical Research Communications·M Kunimoto
Jan 1, 1997·European Journal of Immunology·P MarchettiG Kroemer
Apr 29, 1998·Annual Review of Physiology·G KroemerM Resche-Rigon
Jul 22, 1998·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·R GattiG C Gazzola
Oct 18, 2000·Free Radical Biology & Medicine·J ChandraS Orrenius
Jan 10, 2001·Current Opinion in Neurology·K R Mahaffey
Feb 7, 2001·Toxicological Sciences : an Official Journal of the Society of Toxicology·D K ParranS Barone
Apr 27, 2001·FEBS Letters·A J KowaltowskiA E Vercesi
Jul 27, 2001·Brain Research Bulletin·A CampbellG Perry
Jul 27, 2001·Brain Research Bulletin·A F CastoldiL Manzo
Aug 3, 2001·Nature Reviews. Molecular Cell Biology·M Leist, M Jäättelä
Jan 10, 2002·Toxicology and Applied Pharmacology·Tobi L Limke, William D Atchison
Apr 5, 2002·Journal of Inorganic Biochemistry·Marcantonio BragadinAntonio Toninello
Jun 1, 2002·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Erin K Pias, Tak Yee Aw
Jul 2, 2003·Neurotoxicity Research·Coral SanfeliuEduard Rodríguez-Farré
Feb 5, 2004·The Journal of Pediatrics·Philippe GrandjeanPál Weihe
Mar 20, 2004·Nature Reviews. Drug Discovery·Kevin J BarnhamAshley I Bush

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Citations

Sep 14, 2011·Journal of Toxicology·Eman M Alissa, Gordon A Ferns
Feb 22, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Chelsea T TiernanKeith J Lookingland
Apr 24, 2007·Neurotoxicity Research·Carolina JohanssonSandra Ceccatelli
Apr 24, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Stephanie L OndovcikPeter G Wells
Jan 18, 2016·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Arbace OfficiosoCaterina Manna
Jan 24, 2012·Aquatic Toxicology·Ole Jakob NøstbakkenPål A Olsvik
Jul 24, 2010·Toxicology in Vitro : an International Journal Published in Association with BIBRA·D BussolaroC A Oliveira Ribeiro
Aug 13, 2010·Aquatic Toxicology·Karin BergAnders Goksøyr
May 8, 2010·Ecotoxicology and Environmental Safety·Greice M R S LucenaVania M M Ferreira
Nov 3, 2009·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·F H AbdallaM B Moretto
Nov 28, 2009·Micron : the International Research and Review Journal for Microscopy·Jacopo UggeriRita Gatti
Dec 31, 2008·Mutation Research·Rodrigo FrancoMihalis I Panayiotidis
Jul 1, 2008·Environmental Toxicology and Pharmacology·Yongjin LiYong Li
Aug 14, 2012·Journal of Applied Toxicology : JAT·Sairam BellumLouise C Abbott
Jun 20, 2006·The Journal of Nutritional Biochemistry·Jyrki K VirtanenTomi-Pekka Tuomainen
May 11, 2015·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Lidia TagliafierroCaterina Manna
Dec 3, 2014·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·M VázquezV Devesa
Jun 15, 2007·International Journal of Toxicology·Sairam BellumLouise C Abbott

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